This research has two immediate objectives and both rely on a novel approach to the study of peptide helicities. This tool consists of a series reporting conformational templates(RTC's) that can be linked to a peptide at its N-terminus to initiate a helix and monitor its stability. The first objective of this project is the design, testing, and optimization of new capping structures that can be linked to both N and C-termini of peptides to substantially stabilize their helical conformations. The second objective is to define rigorously the functional dependence of fractional helicity on the experimental value of the circular dichroism ellipticity [theta]222 measured for the peptide at 222 nm. NMR methods applied to RCT-peptide conjugates will be used to calibrate [theta]222 definitively.
With this renewal award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Daniel S. Kemp of the Department of Chemistry at the Massachusetts Institute of Technology. The work aims at a complete description at a chemical level of the folding process for the important case of folded peptide helices. Folding in water can convert a highly flexible linear polypeptide, defined by its ordered, linked sequence of particular amino acids, into a compact, relatively rigid structure that can bind tightly to other biomolecules. Understanding the structures and energetics of the folded forms of proteins and shorter polypeptides is a fundamental problem of modern structural biology and bioorganic chemistry. Helices provide key structural subunits formed by local peptide sequences within most globular proteins. Moreover the docking of folded, helical signal peptides to proteins found at cell surfaces have been shown recently to control growth of abnormal cells found in a significant number of human disease states. Success with the objectives of this proposal is expected not only to allow a better predictive understanding of these docking events but also to provide hitherto unavailable practical methods for tuning, controlling and inhibiting such signal processes. The potential relevance to improvements in cancer diagnosis and treatment is significant.
